ABSTRACT Legionella pneumophila is a gram-negative ?-proteobacterial species that is present in water and soil. In these environments, L. pneumophila is able to grow inside a wide variety of protist species. When people inhale aerosols that contain large numbers of L. pneumophila, the organism can infect alveolar macrophages and cause an acute pneumonia called Legionnaires? disease. In both protists and mammalian macrophages, the organism evades anti-microbial mechanisms by altering the trafficking of the Legionella-containing vacuole (LCV) formed following uptake of the organism. The LCV does not interact with the endosomal system as a typical phagosome but avoids fusion with lysosomes. Another well-documented but poorly understood property of the LCV is that it resembles the endoplasmic reticulum. The ability of L. pneumophila to alter the trafficking of the LCV absolutely depends on a Type IVB secretion system (TFBSS) called the Dot/Icm System. The TFBSS translocates proteins called ?effectors? to the host cells and it is widely accepted that together, these effectors are directly responsible for the observed behaviors of the LCV. The genome of the Philadelphia-1 strain of L. pneumophila encodes approximately 300 different effector proteins and deletion of individual effector genes or even as many as 71 effector genes in a single mutant strain, has modest consequences on LCV trafficking and the ability of the bacteria to survive and multiply in mammalian host cells. This supports the idea that the large repertoire of effectors provides a network of overlapping, redundant functions to ensure the success of the organism in a variety of phylogenetically diverse hosts. This extensive functional redundancy makes it exceedingly complex to figure out how the large number of Legionella effectors orchestrates the behavior of the LCV. As an alternative approach to this problem, we looked for host cell functions that are important for intracellular growth of Legionella. We screened for small molecules that act on host cells and block Legionella intracellular growth and protect macrophages from the cytopathic effects of L. pneumophila infection. Many of these small molecules are predicted to affect the dynamics of calcium transport in eukaryotes, especially inhibitors of the major calcium translocating ATPase in the endoplasmic reticulum (SERCA). Because the endoplasmic reticulum is the site of intracellular calcium stores as well as the site of Legionella replication, we wish to test the hypothesis that intracellular calcium dynamics are either important for correct trafficking of the Legionella containing vacuole or are important for as yet unknown aspects of Legionella physiology.